Lecturer: ass. prof. Beley N.N.

Technology of parenteral preparations.

Feature manufacturing of solutions for injections.

PlanPlan1.Peculiarities of the sterile productmanufacturing.

2. Solvents for parenteral preparations.

3. Equipment in manufacturing of parenteral drugs.

4. Process of filling and stoppering of ampoules.

5. Methods of filling and soldering of ampoules.

6. Quality control of parenteral drugs.

All medicines for parenteral use are All medicines for parenteral use are classified as:classified as:

1. Injection drugs.

2. Intravenous infusion drags.

3. Concentrates for injection or intravenous infusion drags.

4. Powders for injection or intravenous infusion drugs.

5. Implants.

Peculiarities of manufacturing of Peculiarities of manufacturing of parenteral preparations parenteral preparations

- should be prepared in aseptic conditions (A/B class of the room by the GMP classifications);- all substances should have quality “for injections”;- solutions should be sterilized by filtra-tion through deep or membrane filters;- some parenteral preparations can contain antimicrobial preservatives (Benzalkonium Chloride, Chlorbutol, Chlorhexidine Gluconate, Thiomersal, Boric Acid, Salicylic Acid, etc.)

Observance of aseptic conditions is necessary during manufacture of all parenteral preparations.

Especially it is important, if parenteral preparations include thermo sensetive substances or substances with antibacterial properties.

Production begins from the Production begins from the preparing of manufacturing:preparing of manufacturing:

• Sanitary preconditioning of production areas

• Preparing of sterile ventilation air

• Preparing of the process equipment and stock

• Preparing of technological clothes

• Preparing of the personnel

All solutions for parenteral All solutions for parenteral administration should comply the administration should comply the

following requirements of the following requirements of the stability:stability:

•Microbiological

•Physical

•Chemical

Parenteral preparations, which Parenteral preparations, which do not expose thermal do not expose thermal

sterilization:sterilization:• parenteral preparations with thermo

sensitive substances (Adrenaline, Aminophylline, Hexamethylenetetramine);

• parenteral preparations with antimicrobial ingredients (Aminazine, Promethazine Hydrochloride (Diprazinum), etc.);

• suspensions for injections;

• emulsions for parenteral administrations (“Lypofundine”, “Lyposine”, “Lipidine”).

The basic principle of the The basic principle of the parenteral preparationsparenteral preparations

stabilizationstabilization• the maximal avoiding some harmful factors of the environment;

• the addition of some excipients;

• using of the hydrolytic resistance glass for containers (type I or II);

• using the modern technological equipment, and especial technological receptions – unhydrous solvents, special methods of substances clearing;

• manufacturing of parenteral preparations in powders and tablets forms.

Groups of solvents for Groups of solvents for preparing of parenteral preparing of parenteral

preparationspreparations - aqueous (water) solvents

- unhydrous solvents, that are divided on such groups:

1. fat oils,

2. monoatomic and multinuclear alcohols,

3. simple and complex ethers,

4. amides,

5. sulfoxides and sulfones, etc.

Solvents for parenteral Solvents for parenteral preparationspreparations

• For preparing parenteral preparations mix of solvents are very often used (mixes of fat oils with benzyl-benzoate).

• They permit to obtain solutions for injections, suspensions and emulsions, which have prolonged action.

• Plants oils are basic unhydrous solvents for production of solutions, which contain substances insoluble in water.

Requirements toRequirements towater for injections water for injections WFI

• Should be sterile and compliances the reference documents;

• Should be maximally purified;

• Should be free from pyrogens;

• pH of the WFI 5,0 - 6,8;

• Amount of the ammonia - no more than 0,00002 %;

• Amount of the solid residue - no more than 0,001 %;

• Expiration date of WFI is 24 hours.

Process of the injection solutions Process of the injection solutions obtaining includes such steps:obtaining includes such steps:

1. Dissolution of medicines substances;

2. Adding of agent for isotonic;

3. Stabilization;

4. Adding of preservatives;

5. Filtering.

Depending on properties of medicinal substances some operations should be excluded.

Reactors, supplied Reactors, supplied with steam jacket and stirrerswith steam jacket and stirrers

Nutsche-filterNutsche-filter

Nutsche FilterNutsche Filter• A typical unit consists of a dished

vessel with a perforated plate. • The entire vessel can be kept at

desired temperature by using a limpet jacket, jacketed bottom dish & stirrer (blade & shaft) through which heat transfer media can flow.

• The vessel can be made completely leak proof for vacuum or pressure service.

Advantage:Advantage:1. Vacuum or pressure filtration possible.2. Inert gas atmosphere can be maintained.3. Very high solvent recovery.4. Considerable saving in manpower5. Solvents are in closed systems, so no toxic

vapors are let off in the atmosphere.6. Personal safety is maintained and heat

transfer surfaces can be provided to maintain filtration temperature.

Druck-filterDruck-filter (Pressure filters) (Pressure filters)

• Pressure filters are semi continuous type machines that enter a wash a cake discharge mode at the end of the filtration cycle.

• The cycle may extend from 5 to 10 minutes for cake filtration application and up to 8 hours or more for the polishing of liquids.

• Our pressure filters are batch operated. The filtration rate is influenced by the properties of the slurry.

KSRChPhI filter KSRChPhI filter

Sterilization by Filtration

is the process exemption of the thermo sensitive substances solutions from microorganisms, their spores, product life (pyrogens) with depth filtration and membrane separation.

Classification of membranes:• Nuclear,• Film,• Powder,• Fibrous,• Composite.

Ampouling of the purified Ampouling of the purified and filtered solution and filtered solution includes such steps:includes such steps:

•Filling up the ampoules with solution.

•Soldering capillaries.

Ways of ampoules fillingWays of ampoules filling

1. Vacuum way – a large number of ampoules are simultaneously filled with solution for injections

2. Syringe technique – each ampoule is filled separately by syringe

3. Type of vacuum way – vapours-condensation

Vacuum methodVacuum method

1. Cassettes with ampoules are placed in airtight device, where solution for filling ampoules and vacuum is created. While the air is pumped from the ampoules.

2. Then vacuum off and solution fills the ampoules.

Dosage of solution in ampoules done by changing the size of rarefaction

Disadvantages of vacuum Disadvantages of vacuum method:method:

1. Impossibility precise dosing of solution;

2. The part of solution remains in the machine, goes for a second filtering, and this leads to additional pollution and uneconomic costs of solution;

3. While sealing (soldering) the capillaries "Black" head are formed at the their end by burning of solution, after sinking into the solution.

4. Between filling and sealing of ampoules is a significant amount of the time, which adversely affects on the purity of the solution.

The advantagesThe advantages of vacuum of vacuum methodmethod::

1. Method should be used for ampoules of different shapes and sizes.

2. There is a group method.

3. It has double pre-eminence – 25000 ampoules per hour at accuracy of dosage

± 10 - 15 %

Syringe method:Syringe method: is carry out by special dosing tool (piston,

membrane).

1. Ampoules are blown by inert gas immediately before filling by solution;

2. Ampoules are filled by solution for injections;

3. Ampoules are blown by inert gas immediately after filling by solution.

AdvantagesAdvantages of syringe of syringe techniquetechnique::

1. High accuracy of dosing (2 %)

2. Short period of time between filling and sealing 5 – 10 c, more shelf life of parenteral drug;

3. Capillary is not moistened by solution, it remains clear, the process of sealing ampoules improves, it is important for thick and viscous solutions.

DisadvantagesDisadvantages of syringe of syringe techniquetechnique::

1. It required complicated equipment

2. It required more stringent requirements for size and shape of capillaries of ampoules.

3. It has less output but shorter technological process.

Vapours-condensation way:Vapours-condensation way: - a type - a type of vacuum method of filling of vacuum method of filling

ampoules. ampoules.

1. Ampoules are slightly cooled before sealing and solution come out from the capillaries.

2. Their ends are immersed in container with a liquid plastic and immediately removed.

3. Drops of plastic harden and clog sealed ampoule with a solution.

Now ampoule soldering is carried Now ampoule soldering is carried out with the help of gas burners out with the help of gas burners

by two main ways:by two main ways:

1. Melting of capillary tips

2. Stretching of capillaries.

In some unusual cases soldering by electric heating or plastic closure may be used.

Melting the tips of the capillaries:Melting the tips of the capillaries: when the ampoule, which is continuously

rotating, heated capillary tip and glass is melted and soldered hole of capillary.

Disadvantages of the method:

1. Sealing of ampoules is followed by influx

2. The formation of sealing cracks in a place that leads to depressurization of ampoules

3. With a thin capillary formation is accompanied by sealing off the hook at the end of the capillary

Disadvantages of the methodDisadvantages of the method4. At the large diameter of the capillary melting

does not occur fully.

5. The method requires strictly for ampoules were one length. Deviation over the length of 1 ml ampoules, sealing quality has deteriorated.

6. Sealing of ampoules filled with a solution, the capillary formed a smell of burning because capillaries ampoules before sealing subjected washing. They are washed by spray nozzles, directing water spray injection holes in the capillaries ampoules.

Stretching of capillaries Stretching of capillaries

the capillary of ampoules are stretched while ampoules are soldered.

Heating of capillaries is conducted in the middle of ampoules, which continuously rotates.

Then part of capillaries with special forceps is stretched with formation filaments.

Filaments is snipped off and melted off, and throw out in waste.

Parameters of solution for Parameters of solution for parenteral administration parenteral administration

qualityquality• The standards of filling (by a syringe) 

• The tightness of containers

• Absence of the particulate matter (visually)

• Content of active substances

• Colour of solution 

• Transparency

In containers to 50 ml the actual volume of solution is controlled by calibrated syringe;

in containers with a capacity of 50 ml or more the actual volume of solution is controlled by calibrated cylinder at 20 ºC.

The actual volume of solution must be more than the nominal volume.